Pharmaceutical raw materials may be plant, animal or other biological products; inorganic elements and compounds; or organic compounds. If the raw material is the subject of a monograph in a pharmacopoeia or national formulary, a minimum acceptable degree of chemical purity is specified in order to ensure consumer safety. Pharmaceutical compositions, which usually include any number of separate components, including the active drug, are typically mixed into a homogeneous mixture. Public safety requires assurance of accuracy in dosages of pharmaceutical medication, and any blending operation of pharmaceutical raw materials generally seeks to achieve complete uniformity and homogeneity.
A hopper may be used to feed pharmaceutical raw material into a mixing device, such as a blender, where the drug is mixed with other ingredients, generally non-pharmaceutically-active components known as excipients, in order to form a dosage form such as a tablet or capsule. During this process, the drug is mixed with suitable excipients such as dextrin, lactose, salt, polymers, celluloses, stearic acid, talc, or other inactive ingredients. The dosage unit can then be packaged as is, or it may be further modified into a more convenient form for administration to a patient, such as a capsule or tablet.
A tableting or encapsulating machine may be used to form the capsule or tablet dosage form. Hoppers can also be used to feed the pharmaceutical raw material (which may be in the form of a granulate or dry blend) into a tableting/encapsulating machine.
However, vibrations that occur during the manufacturing process may cause stratification of the granules within the hopper prior to preparation of the dosage form. Stratification is localized areas of differing drug potencies, and may occur even though the composition within a localized area is itself homogeneous. Stratification may be related to, varying particle size. A consequence of stratification may be a dosage form being prepared with an inaccurate dosage (e.g., a sub-potent or a super-potent product). Accordingly, the mixing of pharmaceutical compositions is a crucial step in processing an active drug into a dosage form.
Generally, the homogeneity of a pharmaceutical composition refers to the distribution of the active drug in the pharmaceutical composition, and the potency of a pharmaceutical composition refers to the amount of the active component in the pharmaceutical composition. Traditionally, the determinations of the homogeneity and potency of a pharmaceutical mixture have been time consuming. In addition, traditional methods measure the homogeneity and potency only of the active component in a pharmaceutical composition and give no information concerning the homogeneity of the non-active components.
It is also important to determine the concentration of the other, non-active components within the pharmaceutical mixture. The concentration of the non-active components in a pharmaceutical mixture is important because it determines the physical properties of the mixture. For example, disintegrants affect the rate of dissolution of a tablet in a recipient's stomach. If the disintegrant is not homogeneously distributed in the pharmaceutical mixture, then the resulting tablets may not dissolve at a uniform rate, thereby potentially resulting in quality, dosing and bioavailability problems. Thus, it is important to measure the homogeneity of all the components of a pharmaceutical mixture because the dispersion of certain components may ultimately affect the physical properties of the final form of the pharmaceutical composition.
Additionally, as noted above, stratification my be associated with uneven distribution of particle size. The result may be quality, dosing and bioavailability problems.
One method of determining the homogeneity and potency of a pharmaceutical mixture involves removing samples of the mixture from various locations along the path of preparation of the pharmaceutical mixture, such as the hoppers and blender, and analyzing these samples for homogeneity and potency. In doing so, a technician must first stop the process, remove samples of the composition mixture and assay those samples in a laboratory. The samples are typically analyzed using a technique such as ultra-violet (UV) spectroscopy or High Performance Liquid Chromatography (HPLC) to determine whether the active pharmaceutical component is uniformly dispersed (is homogeneous) in the mixture and present at an appropriate concentration level. This information reflects the potency of the mixture, and, if the potency of each sample is the same, then the mixture is considered to be homogeneous. However, neither UV nor HPLC analysis establishes the concentration of the non-active components of the mixture. Furthermore, while the samples are taken to the laboratory and analyzed, the blending or dosage formulation process must be put on hold.
Alternatively, infrared spectroscopy, which can be useful in measuring the molecular composition of pharmaceuticals, can also be used to determine the homogeneity and potency of the ingredients of a pharmaceutical mixture. Infrared radiation (IR) may be roughly divided into three wavelength bands: near-infrared radiation, mid-infrared radiation, and far-infrared radiation. Near-infrared radiation (NIR) is radiation having a wavelength between about 750 nm and about 3000 nm. Mid-infrared radiation (MIR) is radiation having a wavelength, between about 3000 nm and about 10,000 nm. Far-infrared radiation (FIR) is radiation having a wavelength between about 10,000 nm and about 1000 μm (1000 μm being the beginning of the microwave region). The desired range may be chosen to suit the analysis being performed.
In general spectrometers (e.g., spectrophotometers) can be divided into two classes: transmittance spectrometers and reflectance spectrometers. In a transmittance spectrometer, light is directed onto a sample, and a detector detects the light which was transmitted through the sample. In contrast, in a reflectance spectrometer, light is directed onto a sample and one or more detectors detect the light which was reflected from the sample. Depending upon its design, a spectrometer may, or may not, be used as both a transmittance and a reflectance spectrometer.
One method of determining the homogeneity and potency of the components of a pharmaceutical mixture using infrared spectrometry is shown in U.S. Pat. No. 5,504,332 to Richmond et al., which purports to disclose a system that uses near infrared technology for analyzing the uniformity and mass balance of the pharmaceutical mixture in order to control the tablet manufacturing process. The system has a library consisting of near infrared spectral scan data of pharmaceutical materials spanning the normal process range. The patent states that the assessment of uniformity of a sample mixture is accomplished by comparison of near infrared spectral information regarding the sample with the library of near infrared spectral scans of acceptable material. However, the pharmaceutical material is not subjected to near infrared analysis while the pharmaceutical material is being manufactured. Rather, it is analyzed in a separate device, e.g, as a tablet or as a sample.
Another method of determining the homogeneity and potency of the components of a pharmaceutical mixture using infrared spectrometry, although only during active mixing within a blender, is shown in U.S. Pat. No. 5,946,088 to Aldridge, which purports to disclose an apparatus for detecting the homogeneity and potency of a mixture of compositions of matter during the mixing process using a spectrometer. The described apparatus has a V-shaped container that rotates about a horizontal axis of rotation during the mixing process, and the wall of the container includes a single aperture at the location in the wall intersecting the axis of rotation of the container. The patent describes that a radiation detector for detecting spectroscopic characteristics of the mixture is rotatably mounted through the inside of a hollow shaft about which the container rotates, and connections to a remote spectroscopic means and computer, including a fiber optic bundle, are made through the rotational shaft. The computer synchronizes the taking of spectroscopic data by the detector with a predetermined single rotational position or multiple rotational positions of the container, as the taking of spectral data at a consistent predetermined point in the rotation of the container, according to this patent, assures a greater degree of accuracy in determining the homogeneity of the mixture being mixed.